Skip to main content

Advertisement

SpringerLink
Log in

Genetic and Epigenetic Associations with NAFLD: Focus on Clinical Decision Making and Novel Concepts in Disease Pathogenesis

  • Fatty Liver Disease (SA Harrison and J George, Section editors)
  • Published:
Current Hepatology Reports Aims and scope Submit manuscript

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a complex liver disease with worldwide prevalence. Its development involves a myriad of factors, including genetic susceptibility and environmental insults. In this review, we summarize new findings about current genome-wide association studies on NAFLD. In addition, we used a strategy of functional enrichment analysis to integrate all the newly discovered loci into common biological pathways and to explore their role in the pathogenesis of NAFLD. Controversies on the application of genetic testing to predict disease severity are discussed and specifically the role of rs738409 in clinical decision making. Finally, we highlighted significant trends and developments in epigenetic changes and microRNAs associated with disease progression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

ALT:

Alanine-aminotransferase

CT:

Computed tomography

GWAS:

Genome-wide association study

IR:

Insulin resistance

MetSyn:

Metabolic syndrome

miRNA:

microRNA

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

PNPLA3:

Patatin-like phospholipase domain containing 3

PPARGC1A:

Peroxisome proliferator-activated receptor gamma coactivator 1α

SNP:

Single nucleotide polymorphism

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Sookoian S, Pirola CJ. The genetic epidemiology of nonalcoholic fatty liver disease: toward a personalized medicine. Clin Liver Dis. 2012;16(3):467–85.

    Article  PubMed  Google Scholar 

  2. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40(12):1461–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Rodriguez B, Torres DM, Harrison SA. Physical activity: an essential component of lifestyle modification in NAFLD. Nat Rev Gastroenterol Hepatol. 2012;9(12):726–31.

    Article  PubMed  Google Scholar 

  4. Eckard C, Cole R, Lockwood J, Torres DM, Williams CD, Shaw JC, et al. Prospective histopathologic evaluation of lifestyle modification in nonalcoholic fatty liver disease: a randomized trial. Ther Adv Gastroenterol. 2013;6(4):249–59.

    Article  Google Scholar 

  5. Cortez-Pinto H, Machado M. Impact of body weight, diet and lifestyle on nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol. 2008;2(2):217–31.

    Article  CAS  PubMed  Google Scholar 

  6. Neuschwander-Tetri BA. Lifestyle modification as the primary treatment of NASH. Clin Liver Dis. 2009;13(4):649–65.

    Article  PubMed  Google Scholar 

  7. Pirola CJ, Gianotti TF, Burgueno AL, Rey-Funes M, Loidl CF, Mallardi P, et al. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut. 2013;62(9):1356–63. This is the first study showing epigenetic changes in mitochondrial DNA having an impact on a human disease.

    Article  CAS  PubMed  Google Scholar 

  8. Sookoian S, Rosselli MS, Gemma C, Burgueno AL, Fernandez GT, Castano GO, et al. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor gamma coactivator 1alpha promoter. Hepatology. 2010;52(6):1992–2000. This is the first human study showing that changes in liver DNA methylation of PGC1A modulate insulin resistance.

    Article  CAS  PubMed  Google Scholar 

  9. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142(7):1592–609.

    Article  PubMed  Google Scholar 

  10. Sookoian S, Castano GO, Pirola CJ. Modest alcohol consumption decreases the risk of non-alcoholic fatty liver disease: a meta-analysis of 43 175 individuals. Gut. 2013. doi:10.1136/gutjnl-2013-305718.

    Google Scholar 

  11. Brunt EM. Pathology of fatty liver disease. Mod Pathol. 2007;20 Suppl 1:S40–8.

    Article  CAS  PubMed  Google Scholar 

  12. Sookoian S, Pirola CJ. Systems biology elucidates common pathogenic mechanisms between nonalcoholic and alcoholic-fatty liver disease. PLoS One. 2013;8(3):e58895.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Stickel F, Hampe J. Genetic determinants of alcoholic liver disease. Gut. 2012;61(1):150–9.

    Article  CAS  PubMed  Google Scholar 

  14. Sookoian S, Castano GO, Burgueno AL, Gianotti TF, Rosselli MS, Pirola CJ. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res. 2009;50(10):2111–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology. 2011;53(6):1883–94.

    Article  CAS  PubMed  Google Scholar 

  16. Chalasani N, Guo X, Loomba R, Goodarzi MO, Haritunians T, Kwon S, et al. Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease. Gastroenterology. 2010;139(5):1567–76, 1576.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011;7(3):e1001324.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Feitosa MF, Wojczynski MK, North KE, Zhang Q, Province MA, Carr JJ, et al. The ERLIN1-CHUK-CWF19L1 gene cluster influences liver fat deposition and hepatic inflammation in the NHLBI Family Heart Study. Atherosclerosis. 2013;228(1):175–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Kitamoto T, Kitamoto A, Yoneda M, Hyogo H, Ochi H, Nakamura T, et al. Genome-wide scan revealed that polymorphisms in the PNPLA3, SAMM50, and PARVB genes are associated with development and progression of nonalcoholic fatty liver disease in Japan. Hum Genet. 2013;132(7):783–92.

    Article  CAS  PubMed  Google Scholar 

  20. Kawaguchi T, Sumida Y, Umemura A, Matsuo K, Takahashi M, Takamura T, et al. Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese. PLoS One. 2012;7(6):e38322.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Yuan X, Waterworth D, Perry JR, Lim N, Song K, Chambers JC, et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet. 2008;83(4):520–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Chambers JC, Zhang W, Sehmi J, Li X, Wass MN, van der Harst P, et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet. 2011;43(11):1131–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Palmer ND, Musani SK, Yerges-Armstrong LM, Feitosa MF, Bielak LF, Hernaez R, et al. Characterization of european ancestry nonalcoholic fatty liver disease-associated variants in individuals of african and hispanic descent. Hepatology. 2013;58(3):966–75.

    Article  CAS  PubMed  Google Scholar 

  24. Hernaez R, McLean J, Lazo M, Brancati FL, Hirschhorn JN, Borecki IB, et al. Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the third national health and nutrition examination survey. Clin Gastroenterol Hepatol. 2013;11(9):1183–90.

    Article  CAS  PubMed  Google Scholar 

  25. Trepo E, Nahon P, Bontempi G, Valenti L, Falleti E, Nischalke HD, et al. Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: evidence from a meta-analysis of individual participant data. Hepatology. 2013. doi:10.1002/hep.26767.

    Google Scholar 

  26. Gerhard GS, Chu X, Wood GC, Gerhard GM, Benotti P, Petrick AT, et al. Next-generation sequence analysis of genes associated with obesity and nonalcoholic fatty liver disease-related cirrhosis in extreme obesity. Hum Hered. 2013;75(2–4):144–51.

    Article  CAS  PubMed  Google Scholar 

  27. Cefalu AB, Pirruccello JP, Noto D, Gabriel S, Valenti V, Gupta N, et al. A novel APOB mutation identified by exome sequencing cosegregates with steatosis, liver cancer, and hypocholesterolemia. Arterioscler Thromb Vasc Biol. 2013;33(8):2021–5.

    Article  CAS  PubMed  Google Scholar 

  28. Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 2010;38(Web Server issue):W214–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Mignery GA, Pikaard CS, Park WD. Molecular characterization of the patatin multigene family of potato. Gene. 1988;62(1):27–44.

    Article  CAS  PubMed  Google Scholar 

  30. Jenkins CM, Mancuso DJ, Yan W, Sims HF, Gibson B, Gross RW. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J Biol Chem. 2004;279(47):48968–75.

    Article  CAS  PubMed  Google Scholar 

  31. Sookoian S, Pirola CJ. PNPLA3, the triacylglycerol synthesis/hydrolysis/storage dilemma, and nonalcoholic fatty liver disease. World J Gastroenterol. 2012;18(42):6018–26.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Kim TS, Sundaresh CS, Feinstein SI, Dodia C, Skach WR, Jain MK, et al. Identification of a human cDNA clone for lysosomal type Ca2 + -independent phospholipase A2 and properties of the expressed protein. J Biol Chem. 1997;272(4):2542–50.

    Article  CAS  PubMed  Google Scholar 

  33. Blom N, Gammeltoft S, Brunak S. Sequence and structure-based prediction of eukaryotic protein phosphorylation sites. J Mol Biol. 1999;294(5):1351–62.

    Article  CAS  PubMed  Google Scholar 

  34. He S, McPhaul C, Li JZ, Garuti R, Kinch L, Grishin NV, et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem. 2010;285(9):6706–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Li JZ, Huang Y, Karaman R, Ivanova PT, Brown HA, Roddy T, et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest. 2012;122(11):4130–44.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Perttila J, Huaman-Samanez C, Caron S, Tanhuanpaa K, Staels B, Yki-Jarvinen H, et al. PNPLA3 is regulated by glucose in human hepatocytes, and its I148M mutant slows down triglyceride hydrolysis. Am J Physiol Endocrinol Metab. 2012;302(9):E1063–9.

    Article  CAS  PubMed  Google Scholar 

  37. Pirazzi C, Adiels M, Burza MA, Mancina RM, Levin M, Stahlman M, et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J Hepatol. 2012;57(6):1276–82.

    Article  CAS  PubMed  Google Scholar 

  38. Sookoian S, Pirola CJ. PNPLA3, the history of an orphan gene of the potate tuber protein family that found an organ: the Liver. Hepatology. 2013. doi:10.1002/hep.26895.

    Google Scholar 

  39. Kotronen A, Peltonen M, Hakkarainen A, Sevastianova K, Bergholm R, Johansson LM, et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology. 2009;137(3):865–72.

    Article  CAS  PubMed  Google Scholar 

  40. Francque SM, Verrijken A, Mertens I, Hubens G, Van ME, Pelckmans P, et al. Noninvasive assessment of nonalcoholic fatty liver disease in obese or overweight patients. Clin Gastroenterol Hepatol. 2012;10(10):1162–8.

    Article  PubMed  Google Scholar 

  41. Guichelaar MM, Gawrieh S, Olivier M, Viker K, Krishnan A, Sanderson S, et al. Interactions of allelic variance of PNPLA3 with nongenetic factors in predicting nonalcoholic steatohepatitis and nonhepatic complications of severe obesity. Obesity (Silver Spring). 2013;21(9):1935–41.

    CAS  Google Scholar 

  42. Adams LA, Feldstein AE. Non-invasive diagnosis of nonalcoholic fatty liver and nonalcoholic steatohepatitis. J Dig Dis. 2011;12(1):10–6.

    Article  CAS  PubMed  Google Scholar 

  43. Sookoian S, Castano G, Burgueno AL, Gianotti TF, Rosselli MS, Pirola CJ. A diagnostic model to differentiate simple steatosis from nonalcoholic steatohepatitis based on the likelihood ratio form of Bayes theorem. Clin Biochem. 2009;42(7–8):624–9.

    Article  PubMed  Google Scholar 

  44. Hassan MM, Kaseb A, Etzel CJ, El-Serag H, Spitz MR, Chang P, et al. Genetic variation in the PNPLA3 gene and hepatocellular carcinoma in USA: Risk and prognosis prediction. Mol Carcinog. 2013;52 Suppl 1:139–47.

    Article  Google Scholar 

  45. Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429(6990):457–63.

    Article  CAS  PubMed  Google Scholar 

  46. Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009;10(5):295–304.

    Article  CAS  PubMed  Google Scholar 

  47. Burgueno AL, Cabrerizo R, Gonzales MN, Sookoian S, Pirola CJ. Maternal high-fat intake during pregnancy programs metabolic-syndrome-related phenotypes through liver mitochondrial DNA copy number and transcriptional activity of liver PPARGC1A. J Nutr Biochem. 2013;24(1):6–13.

    Article  CAS  PubMed  Google Scholar 

  48. Ventura-Clapier R, Garnier A, Veksler V. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res. 2008;79(2):208–17.

    Article  CAS  PubMed  Google Scholar 

  49. Sookoian S, Pirola CJ. DNA methylation and hepatic insulin resistance and steatosis. Curr Opin Clin Nutr Metab Care. 2012;15(4):350–6.

    Article  CAS  PubMed  Google Scholar 

  50. Gianotti TF, Sookoian S, Dieuzeide G, Garcia SI, Gemma C, Gonzalez CD, et al. A decreased mitochondrial DNA content is related to insulin resistance in adolescents. Obesity. 2008;16(7):1591–5.

    Article  CAS  PubMed  Google Scholar 

  51. Gemma C, Sookoian S, Alvarinas J, Garcia SI, Quintana L, Kanevsky D, et al. Mitochondrial DNA depletion in small- and large-for-gestational-age newborns. Obesity (Silver Spring). 2006;14(12):2193–9.

    Article  CAS  Google Scholar 

  52. Gemma C, Sookoian S, Alvarinas J, Garcia SI, Quintana L, Kanevsky D, et al. Maternal pregestational BMI is associated with methylation of the PPARGC1A promoter in newborns. Obesity (Silver Spring). 2009;17(5):1032–9.

    Article  CAS  Google Scholar 

  53. Sookoian S, Gianotti TF, Burgueno AL, Pirola CJ. Fetal metabolic programming and epigenetic modifications: a systems biology approach. Pediatr Res. 2013;73(4 Pt 2):531–42.

    Article  CAS  PubMed  Google Scholar 

  54. Ahrens M, Ammerpohl O, von Schönfels W, Kolarova J, Bens S, Itzel T, et al. DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. Cell Metab. 2013;18(2):296–302. Human study showing the potential reversibility of epigenetic changes after therapeutic intervention.

    Article  CAS  PubMed  Google Scholar 

  55. Murphy SK, Yang H, Moylan CA, Pang H, Dellinger A, Abdelmalek MF, et al. Relationship between methylome and transcriptome in patients with nonalcoholic Fatty liver disease. Gastroenterology. 2013;145(5):1076–87. This study explored methylation marks and its relationship with the disease severity.

    Article  CAS  PubMed  Google Scholar 

  56. Pirola CJ, Gianotti TF, Castano GO, Sookoian S. Circulating MicroRNA-122 signature in nonalcoholic fatty liver disease and cardiovascular disease: a new endocrine system in metabolic syndrome. Hepatology. 2013;57(6):2545–7.

    Article  CAS  PubMed  Google Scholar 

  57. Cermelli S, Ruggieri A, Marrero JA, Ioannou GN, Beretta L. Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS One. 2011;6(8):e23937.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Yamada H, Suzuki K, Ichino N, Ando Y, Sawada A, Osakabe K, et al. Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver. Clin Chim Acta. 2013;424:99–103.

    Article  CAS  PubMed  Google Scholar 

  59. Min HK, Kapoor A, Fuchs M, Mirshahi F, Zhou H, Maher J, et al. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab. 2012;15(5):665–74.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Pirola CJ, Fernandez GT, Burgueno AL, Castano G, Sookoian S. Circulating micro-RNA Profile in nonalcoholic fatty liver disease: potential biomarkers and its role in the modulation of the metabolic syndrome? Hepatology. 2013;58(suppl):247A.

    Google Scholar 

  61. Cheung O, Puri P, Eicken C, Contos MJ, Mirshahi F, Maher JW, et al. Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression. Hepatology. 2008;48(6):1810–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Sookoian S, Gianotti TF, Rosselli MS, Burgueno AL, Castano GO, Pirola CJ. Liver transcriptional profile of atherosclerosis-related genes in human nonalcoholic fatty liver disease. Atherosclerosis. 2011;218(2):378–85.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was partially supported by grants PICT 2010-0441 and PICT 2012-0159 (Agencia Nacional de Promoción Científica y Tecnológica), and UBACYT CM04 (Universidad de Buenos Aires). SS and CJP belong to Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET).

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Silvia Sookoian declares no conflicts of interest.

Carlos J. Pirola is a paid board member, receives honoraria, and receives travel/accomodation expenses from Merck Sharp and Dohm.

Human and Animal Rights and Informed Consent

All the investigations performed in this study and related articles were conducted in accordance with the guidelines of the 1975 Declaration of Helsinki. Written consent from individuals was obtained in accordance with the procedures approved by the Ethical Committee of our institution.

Author information

Authors and Affiliations

  1. Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires – National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina

    Silvia Sookoian

  2. Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires – National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina

    Carlos J. Pirola

  3. Instituto de Investigaciones Médicas A. Lanari-CONICET, Combatiente de Malvinas 3150, Buenos Aires, 1427, Argentina

    Silvia Sookoian & Carlos J. Pirola

Authors
  1. Silvia Sookoian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carlos J. Pirola
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Silvia Sookoian or Carlos J. Pirola.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sookoian, S., Pirola, C.J. Genetic and Epigenetic Associations with NAFLD: Focus on Clinical Decision Making and Novel Concepts in Disease Pathogenesis. Curr Hepatology Rep 13, 97–105 (2014). https://doi.org/10.1007/s11901-014-0222-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11901-014-0222-x

Keywords

Search

Navigation